Differential requirements for survivin in hematopoietic cell development
Differential requirements for survivin in hematopoietic cell development
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DOI：
10.1073/pnas.0500303102
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发表时间：
2005-08-09
影响因子：
11.1
通讯作者：
Crispino, JD
中科院分区：
文献类型：
--
作者：
Gurbuxani, S;Xu, YF;Crispino, JD
尽管红细胞和巨核细胞来自共同的祖细胞，但它们的最终成熟遵循截然不同的路径。红系细胞经历细胞周期退出和去核，而巨核细胞在细胞周期中继续前进，但跳过有丝分裂的后期阶段，成为多倍体细胞。在我们努力鉴定参与这一过程的基因的过程中，我们发现生存素是细胞凋亡抑制剂家族的成员，在胞质分裂中也起着重要作用，在红细胞和巨核细胞发育过程中表达存在差异。红系细胞在其成熟过程中表达生存素，而巨核细胞表达的生存素 mRNA 水平低约 4 倍，并且没有可检测到的蛋白质。为了研究生存素在这些谱系中的作用，我们从小鼠骨髓细胞中过度表达或敲低生存素，然后检查红细胞和巨核细胞的发育。这些研究表明，生存素的过度表达会拮抗巨核细胞的生长、成熟和多倍化，但对红细胞发育没有影响。这种多倍体化的阻断伴随着 p21 表达的增加和巨核细胞基因（如冯维勒布兰德因子和 β(1)-微管蛋白）表达的减少。相反，生存素表达的减少会干扰红细胞的形成，但不会干扰巨核细胞。最后，与增殖细胞存活所需的生存素一致，缺乏生存素的造血祖细胞无法产生红细胞集落或巨核细胞集落。总之，这些研究表明，虽然生存素表达对于巨核细胞和红系祖细胞至关重要，但其下调是巨核细胞终末分化所必需的。
Although erythroid cells and megakaryocytes arise from a common progenitor, their terminal maturation follows very different paths; erythroid cells undergo cell-cycle exit and enucleation, whereas megakaryocytes continue to progress through the cell cycle but skip late stages of mitosis to become polyploid cells. In our efforts to identify genes that participate in this process, we discovered that survivin, a member of the inhibitor of apoptosis family that also has an essential role in cytokinesis, is differentially expressed during erythroid versus megakaryocyte development. Erythroid cells express survivin throughout their maturation, whereas megakaryocytes express approximate to 4-fold lower levels of survivin mRNA and no detectable protein. To investigate the role of survivin in these lineages, we overexpressed or knocked down survivin from mouse bone marrow cells and then examined erythroid and megakaryocyte development. These studies revealed that overexpression of survivin antagonized megakaryocyte growth, maturation, and polyploidization but had no effect on erythroid development. This block in polyploidization was accompanied by increased expression of p21 and decreased expression of megakaryocyte genes such as von Willebrand factor and beta(1)-tubulin. In contrast, a reduction in survivin expression interfered with the formation of erythroid cells but not megakaryocytes. Last, consistent with the requirement for survivin in the survival of proliferating cells, survivin-deficient hematopoietic progenitors failed to give rise to either erythroid or megakaryocytic colonies. Together, these studies show that whereas survivin expression is essential for megakaryocyte and erythroid progenitors, its down-regulation is required for terminal differentiation of megakaryocytes.